1. Field of the Invention
The present invention relates to a pulsed signal generator for biomedical applications. In particular, the present invention relates to a light-weight, compact pulsed signal generator that produces an output waveform based on at least four timing intervals T1-T4, more preferably, a waveform based on seven timing intervals T1-T7.
2. Discussion of Background
Injuries, infections and degenerative conditions are major sources of pain, inconvenience, expense, lost work (and leisure) time and diminished productivity. The problems associated with these conditions grow worse with age, since an injury which would heal quickly in a young, healthy person takes much longer in one who is older, in poor health, or both. In demographically-aging societies such as now seen in most of the industrialized nations, these social and economic impacts will become increasingly magnified over the course of the next several decades.
While it is difficult to estimate the total cost of such conditionsxe2x80x94leaving aside their impact on quality of lifexe2x80x94the total surely amounts to many billions of dollars per year in the United States alone. For example, between five and ten million United States residents suffer broken bones every year, with many of these cases involving multiple fractures. In a young, healthy patient, many fractures need to be immobilized in a cast for six weeks or more. Even after the cast is removed, the patient""s activities are frequently restricted until the healed bone regains its full strength. In the elderly, in persons with poor health or malnutrition, in patients with multiple fractures, or in patients with conditions that impact healing processes, fractures heal more slowly. In some cases, the fractures do not heal at all, resulting in the conditions known as xe2x80x9cnonunionxe2x80x9d or xe2x80x9cnonunion fracturexe2x80x9d which sometimes persists for a lifetime.
As a result, an estimated quarter-million person-years of productivity are lost in the United States due to bone fractures alone. Similar statistics can be generated not only for other classes of traumatic injury, but also for chronic conditions such as osteoarthritis, osteoporosis, diabetic and decubitus ulcers, damaged ligaments, tendonitis, and repetitive stress injuries (including the conditions commonly known as xe2x80x9ctennis elbowxe2x80x9d and carpal tunnel syndrome).
Since the 1960s, it has been increasingly recognized that the human body generates a host of low-level electric signals as a result of injury, stress and other factors; that these signals play a necessary part in healing and disease-recovery processes; and that such processes can be accelerated by providing artificially-generated signals which mimic the body""s own in frequency, waveform and strength. Such xe2x80x9cmimicxe2x80x9d signals can speed the healing of skin and muscle wounds, including chronic ulcers such as those resulting from diabetes; the mending of broken bones, including most nonunion fractures; the regrowth of injured or severed nerves; and the repair of tissues damaged by repetitive motion, as in tendonitis and osteoarthritis. xe2x80x9cMimicxe2x80x9d signals can also reduce swelling, inflammation, and especially pain, including chronic pain for which the usual drug-based treatments no longer bring satisfactory relief.
Some of the body""s signals, such as the xe2x80x9cinjury potentialxe2x80x9d or xe2x80x9ccurrent of injuryxe2x80x9d measured in wounds, are DC (direct current) only, changing slowly with time. It has been found that bone fracture repair and nerve regrowth are typically faster than usual in the vicinity of a negative electrode but slower near a positive one, where in some cases tissue atrophy or necrosis may occur. For this reason, most recent research has focused on higher-frequency, more complex signals often with no net DC component.
While most complex-signal studies to date have been performed on bone fracture healing, the commonality of basic physiological processes in all tissues suggests that the appropriate signals will be effective in accelerating many other healing and disease-recovery processes. Indeed, specific frequency and waveform combinations have been observed to combat osteoarthritis and insomnia, stimulate hair growth, reduce swelling and inflammation, fight localized infection, speed the healing of injured soft tissues including skin, nerves, ligaments and tendons, and relieve pain without the substituted discomfort of TENS (transcutaneous electric nerve stimulation).
FIGS. 1A and 1B show a schematic view of a waveform 20 which has been found effective in stimulating bone fracture healing, where a line 22 (FIG. 1A) represents the waveform on a short time scale, a line 24 (FIG. 1B) represents the same waveform on a longer time scale, levels 26 and 28 represent two different characteristic values of voltage or current, and intervals 30, 32, 34 and 36 represent the timing between specific transitions. Levels 26 and 28 are selected so that, when averaged over a full cycle of the waveform, there is no net DC component. In real-world applications, waveform 20 is typically modified in that all voltages or currents decay exponentially toward some intermediate level between levels 26 and 28, with a decay time constant usually on the order of interval 34. The result is represented by a line 38 (FIG. 1C).
In a typical commercially-available device for treating fracture nonunions, interval 30 is about 200 xcexcsec, interval 32 about 30 xcexcsec, interval 34 about 5 msec, and interval 36 about 60 msec. Alternate repetition of intervals 30 and 32 generates pulse bursts 40, each of the length of interval 34, separated by intervals of length 36 in which the signal remains approximately at level 28. Each waveform 38 thus consists of rectangular waves alternating between levels 26 and 28 at a frequency of about 4400 Hz and a duty cycle of about 85%. The pulse bursts are repeated at a frequency of about 15 Hz and a duty cycle of about 7.5%, alternating with periods of substantially no signal. The timing of such a signal can vary broadly, since the characteristics of signals generated by bone in vivo and in vitro depend on a number of factors, including but not necessarily limited to its type, size and mineral density, and the amount of stress and its rate of application. Hence, osteoblasts are believed to be able to respond to a range of signals which differ somewhat in waveform and frequency content.
However, different tissues may respond differently to markedly different frequencies and waveforms. For example, the waveform of FIGS. 1A-C is effective in speeding the healing of a bone fracture but much less so in slowing the progress of osteoporosis. On the other hand, a waveform 50 (FIG. 2) consisting of single pulses 52 of polarity 26 lasting approximately 350-400 xcexcsec each, alternating with intervals 54 of polarity 28 at a frequency of approximately 60-75 Hz, can slow or even reverse osteoporosis but has little effect on fracture repair. Again, the exact waveform and frequency for each application may vary.
The signal intensity may also vary; indeed, more powerful signals often give no more benefit than weaker ones, and sometimes less. This paradoxical relationship is shown schematically in FIG. 3, where a line 60 represents the magnitude of the healing effect at various signal intensities. For a typical signal (such as the signal of FIGS. 1A-C), a peak effectiveness 62 typically falls somewhere between one and ten xcexcA/cm2, and a crossover point 64 at about a hundred times this value. Beyond point 64, the signal may slow healing or may itself cause further injury. Similar responses are seen in other biological processes that are responsive to electrical stimulation, including cell division, protein and DNA synthesis, gene expression, and intracellular second-messenger concentrations. For example, while conventional TENS can block pain perception with a relatively strong signal, much as a jamming signal blocks radio communication, it can also lead to progressively worsening injury.
The important factors for most healing applications appears to be that the high-frequency signal appears in bursts, separated by longer intervals of quiet or no signalxe2x80x94i.e., the duty cycle is relatively lowxe2x80x94and that the waveform within these bursts is itself asymmetric. Results appear to be better when frequency components above about 50 KHz are filtered out, giving transition times on the order of five xcexcsec. Tests using sine waves, square waves, frequencies above about 50 KHz, or waveforms generally resembling that in FIG. 1 but with duty cycles approaching 50% or with excessively fast or slow rise times, have shown much lower effectiveness at otherwise-comparable power levels.
Many different types of electrical stimulation devices are available to consumers and medical professionals, producing many different waveforms ranging from constant-current or constant voltage (DC) through low-frequency to high frequency waveforms. In general, the lower-frequency waveforms and high-frequency pulses within a low-frequency envelope tend to be aimed at tissue-healing applications, while higher-frequency waveforms are used for pain relief
Electrical stimulation is widely used in tissue healing applications. Here, Petrofsky (U.S. Pat. No. 5,974,342) shows a microprocessor-controlled apparatus for treating injured tissue, tendon, or muscle by applying a therapeutic current. The apparatus has several channels that provide biphasic constant voltage or current, including a 100-300 xcexcsec positive phase, a 200-750 xcexcsec inter-phase, and a 100-300 xcexcsec negative phase occurring once every 12.5-25 msec.
Pilla, et al. (U.S. Pat. No. 5,723,001) disclose an apparatus for therapeutically treating human body tissue with pulsed radiofrequency electromagnetic radiation. The apparatus generates bursts of pulses having a frequency of 1-100 MHz, with 100-100,000 pulses per burst, and a burst repetition rate of 0.01-1000 Hz. The pulse envelope can be regular, irregular, or random.
Bartelt, et al. (U.S. Pat. No. 5,117,826) discloses an apparatus and method for combined nerve fiber and body tissue stimulation. The apparatus generates biphasic pulse pairs for nerve fiber stimulation, and a net DC stimulus for body tissue treatment (provided by biphasic pulse trains having a greater number of negative than positive pulses). In U.S. Pat. No. 4,895,154, Bartelt, et al. describe a device for stimulating enhanced healing of soft tissue wounds that includes a plurality of signal generators for generating output pulses. The intensity, polarity, and rate of the output pulses can be varied via a series of control knobs or switches on the front panel of the device.
Gu, et al. (U.S. Pat. No. 5,018,525) show an apparatus that generates a pulse train made up of bursts having the same width, where each burst is made up of a plurality of pulses of a specific frequency. The number of pulses varies from one burst to the next; the frequency of the pulses in each burst varies from one burst to the next corresponding to the variation in the number of pulses in each burst. The pulses have a frequency of 230-280 KHz; the duty cycle of the bursts is between 0.33% and 5.0%.
Liss, et al. (U.S. Pat. No. 5,109,847) relates to a portable, non-invasive electronic apparatus which generates a specifically contoured constant current and current-limited waveform including a carrier frequency with at least two low-frequency modulations. The carrier frequency is between 1-100,000 KHz, square-wave or rectangular-wave modulating frequencies are 0.01-199 KHz and 0.1-100 KHz. Duty cycles may vary, but are typically 50%, 50%, and 75% for the three waveforms.
Borkan""s tissue stimulator (U.S. Pat. No. 4,612,934) includes an implantable, subcutaneous receiver and implantable electrodes. The receiver can be noninvasively programmed after implantation to stimulate different electrodes or change stimulation parameters (polarity and pulse parameters) in order to achieve the desired response; the programming data is transmitted in the form of a modulated signal on a carrier wave. The programmed stimulus can be modified in response to measured physiological parameters and electrode impedance.
Hondeghem (U.S. Pat. No. 4,255,790) describes a programmable pulse generating system where the time periods and sub-intervals of the output pulses are defined by signals from a fundamental clock frequency generation circuit, plus a pair of parallel sets of frequency division circuits connected to that circuit. The time periods, sub-intervals, and output waveforms are variable.
Hsiang-Lai, et al. (U.S. Pat. No. 3,946,745) provide an apparatus for generating positive and negative electric pulses for therapeutic purposes. The apparatus generates a signal consisting of successive pairs of pulses, where the pulses of each pair are of opposite polarities. The amplitude, duration, the interval between the pulses of each pair, and the interval between successive pairs of pulses are independently variable.
McDonald (U.S. Pat. No. 3,589,370) shows an electronic muscle stimulator which produces bursts of bidirectional pulses by applying unidirectional pulses to a suitable transformer.
Landauer (U.S. Pat. No. 3,294,092) discloses an apparatus that produces electrical currents for counteracting muscle atrophy, defects due to poor nutrition, removing exudates, and minimizing the formation of adhesions. The amplitude of the output signals is variable.
Kronberg (U.S. Pat. Nos. 5,217,009, 5,413,596, 6,011,994, and application Ser. No. 09/478,103 (filed Jan. 1, 2000), all incorporated herein by reference) describes signal generators for biomedical applications. The generators produce pulsed signals having fixed and variable amplitude, fixed, variable, and swept frequencies, and (in some cases) optional DC biasing.
Units designed for use in transcutaneous electroneural stimulation (xe2x80x9cTENSxe2x80x9d) for pain relief are widely available. For example, Bastyr, et al. (U.S. Pat. No. 5,487,759) disclose a battery-powered device that can be used with different types of support devices that hold the electrode pads in position. Keyed connectors provide a binary code that is used to determine what type of support device is being used for impedance matching and carrier frequency adjustment. The carrier frequency is about 2.5-3.0 KHz, the therapeutic frequency is typically on the order of 2-100 Hz.
Kolen (U.S. Pat. No. 5,350,414) provides a device where the carrier pulse frequency, modulation pulse frequency, intensity, and frequency/amplitude modulation are controlled by a microprocessor. The device includes a pulse modulation scheme where the carrier frequency is matched to the electrode-tissue load at the treatment site to provide more efficient energy transfer.
Liss, et al. (U.S. Pat. No. 4,784,142) discloses an electronic dental analgesia apparatus and method. The apparatus generates a output with relatively high frequency (12-20 KHz) pulses with nonsymmetrical low frequency (8-20 Hz) amplitude modulation.
Bartelt, et al. (U.S. Pat. No. 5,063,929) describe a microprocessor-controlled device that generates biphasic constant-current output pulses. The stimulus intensity can be varied by the user.
Charters, et al. (U.S. Pat. No. 4,938,223) provide a device with an output signal consisting of bursts of stimuli with waxing and waning amplitudes, where the amplitude of each stimulus is a fixed percentage of the amplitude of the burst. The signal is amplitude-modulated to help prevent the adaptation response in patients.
Molina-Negro, et al. (U.S. Pat. No. 4,541,432) disclose an electric nerve stimulation device for pain relief The device produces a bipolar rectangular signal with a preselected repetition rate and width for a first time period. Then, a rectangular signal is generated at a pseudo-random rate for a second time period, and delivery of the signal is inhibited for a third, pseudo-random period of time. This protocol is said to substantially eliminate adaptation of nerve sells to the stimulation.
Butler, et al. (U.S. Pat. No. 4,431,000) show a transcutaneous nerve stimulator for treating aphasias and other neurologically-based speech and language impairments. The device uses a pseudorandom pulse generator to produce an irregular pulse train composed of trapezoidal, monophasic pulses which mimic typical physiological wave forms (such as the brain alpha rhythm). A series of such pulses has a zero DC level; a current source in the device reduces the effects of variables such as skin resistance.
Maurer (U.S. Pat. No. 4,340,063) discloses a stimulation device which can be implanted or applied to the body surface. The amplitude of the pulse decreases with a degradation in pulse width along a curve defined by a hyperbolic strength-duration curve. This is said to result in proportionately greater recruitment of nerve fibers due to the nonlinear relationship between pulse width and threshold.
The Kosugi, et al. system (U.S. Pat. No. 4,338,945) generates pulses that fluctuate in accordance with the 1/f rule. That is, the spectral density of the fluctuation varies inversely with the frequency: pleasant stimuli often have stochastic fluctuations governed by this rule. The system produces an irregular pulse train said to promote patient comfort during the stimulation.
Signal generators are also used in hearing prostheses. For example, McDermott""s receiver/stimulator (U.S. Pat. No. 4,947,844) generates a series of short spaced current pulses, with between-pulse intervals of zero current having a duration longer than that of each spaced pulse. The waveform of the stimulus current includes a series of these spaced pulses of one polarity followed by an equal number of spaced pulses of opposite polarity so that the sum of electrical charge transferred through the electrodes is approximately zero.
Alloca (U.S. Pat. No. 4,754,7590 describes a neural conduction accelerator for generating a train of xe2x80x9cstaircase-shapedxe2x80x9d pulses whose peak negative amplitude is two-thirds of the peak positive amplitude. The accelerator design is based on Fourier analysis of nerve action potentials; the output frequency can be varied between 1-1000 Hz.
Galbraith (U.S. Pat. No. 4,592,359) describes a multi-channel implantable neural stimulator wherein each data channel is adapted to carry information in monopolar, bipolar, or analog form. The device includes charge balance switches designed to recover residual charge when the current sources are turned off (electrode damage and bone growth are said to be prevented by not passing DC current or charge).
Despite its great healing potential, traditional Western medicine has accepted electrotherapeutic treatment only grudgingly, and to date it is used only rarely. This seems to be a legacy from early beliefs that signals would need to have high local intensities to be effective. Most electrotherapeutic apparatus now available relies either on direct implantation of electrodes or entire electronic packages, or on inductive coupling through the skin. The need for surgery and biocompatible materials in the one case, and excessive circuit complexity and input power in the other, has kept the price of most such apparatus (apart from TENS devices) relatively high, and has also restricted its application to highly trained personnel. There remains a need for a versatile, cost-effective apparatus that can be used to provide bioelectric stimulation in a wide range of applications, including healing acceleration and pain relief
According to its major aspects and broadly stated, the present invention is an apparatus and method for generating an electrical signal for use in biomedical applications. The signal is based on at least four timing intervals T1-T4; more preferably, the signal is based on seven timing intervals T1-T7. The apparatus includes a first timing block for generating timing intervals T1 and T2; a second timing block for generating timing intervals T3 and T4 (the timing blocks also generate intervals T5, T6, and T7 if present); an interconnection block for combining these intervals into an output signal having predetermined relationships among the intervals; an output block for transmitting the output signal to a load, a battery pack; and, optionally, a filter for removing unwanted frequency components from the output signal; and an adjustment block for selecting from among a plurality of output signals with predetermined characteristics. The signal has a first amplitude level L1 during intervals T1, T5, and T6, a second level L2 during intervals T2 and T4, and a third level L3 during interval T7, where L3 falls in the range between L1 and L2, inclusive.
The apparatus is lightweight, compact, self-contained, cost-effective to manufacture and maintain, and convenient to carry or wear for extended periods. It is safe for unsupervised home use without the need for special training, and able to generate the above-described output signal and deliver it efficiently through conductive pads making direct contact with the load. Since only low voltages and currents are used, the apparatus does not pose a shock hazard even in case of malfunction. Power is furnished by compact and inexpensive batteries, needing replacement only once in several weeks of use.
The apparatus may be used to provide electrotherapeutic treatment for human and animal patients, including but not necessarily limited to healing acceleration, relief of acute or chronic pain, and relief of swelling and/or inflammation. Since isolated cells or tissue cultures can also be affected by electrotherapeutic waveforms (appropriate electrical stimuli have been observed to modify the rates of cell metabolism, secretion, and replication), the apparatus may also be used for in vitro applications.
The output signal is an important feature of the present invention. The output signal is a waveform based on at least four timing intervals T1-T4 having the following relationships:
(a) (2xc3x97T2)xe2x89xa6T1xe2x89xa6(20xc3x97T2)
(b) (50 xcexcsecxe2x89xa6(T1+T2)xe2x89xa65000 xcexcsec
(c) T3xe2x89xa7(10xc3x97T1)
(d) T4xe2x89xa6500 msec
where the signal has a first amplitude level L1 during interval T1 and a second amplitude level L2 during intervals T2 and T4, where intervals T1 and T2 alternate through interval T3, and where intervals T3 and T4 also alternate. Thus, intervals T1 and T2 are analogous to intervals 30 and 32 of FIG. 1A; intervals T3 and T4 are analogous to intervals 34 and 36 of FIG. 1B.
More preferably, the waveform is based on seven timing intervals T1-T7, with three different amplitude levels as described above. The timing intervals have, approximately, the following relationships:
(a) (2xc3x97T2)xe2x89xa6T1xe2x89xa6(20xc3x97T2)
(b) 50 xcexcsecxe2x89xa6(T1+T2)xe2x89xa65000 xcexcsec
(c) T3xe2x89xa7(10xc3x97T1)
(d) 0xe2x89xa6T4xe2x89xa6500 msec
(e) 0xe2x89xa6T5xe2x89xa6T1 
(f) 0xe2x89xa6T6xe2x89xa6T1 
(g) 0xe2x89xa6T7xe2x89xa6500 msec
(h) 5 msecxe2x89xa6(T3+T4+T7)xe2x89xa6500 msec
In a preferred embodiment, interval T3 consists of the following sequence: an interval T5, followed by at least one pair of intervals (T1, T2), and then by an interval T6. The timing intervals and amplitude levels are variable, providing an output signal that can be adjusted for a wide range of therapeutic applications.
The apparatus is another important feature of the present invention. The apparatus includes timing blocks (such as oscillators or astable multivibrators) for generating the timing intervals, preferably connected so that the first timing block controls the second timing block through the interconnection block. Preferably, the apparatus includes a switching block that enables the user to select from among a plurality of paired values of intervals (T1, T2), and a plurality of paired values of intervals (T3, T4), and amplitude output levels L1-L3. More preferably, the transition between any two of levels L1 through L3 has a decay time constant no greater than approximately xc2xd T2. Optionally, the apparatus may produce a waveform wherein all amplitude levels decay towards a value L4 intermediate between L1 and L2 (in like manner to the signals shown in FIG. 1C). In this case, L4 may or may not be equal to L3, and the decay takes place with a time constant no less than approximately 10 times T1. Thus, the output signal is adjustable in both waveform and amplitude to suit the needs of the individual user and the particular application.
Another feature of the present invention is the provision of interval T7, during which intermediate voltage or current level L3 is presented to the load rather than low level L2. This feature minimizes the amount of low-frequency energy which is presented to the load (such as tissue being treated with the apparatus) during this resting interval between pulse bursts.
Still another feature of the present invention is the filter, which blocks frequencies above a selected level (i.e., frequencies greater than the highest ones intentionally generated), to create a desired transition profile or to prevent interference by external high-frequency signal sources. For example, the filter may include a shunt capacitance, a resistor network, a voltage-controlled current source, or other suitable device that simultaneously slows and controls the rate of transitions, attenuates output frequency components above about 50 KHz (or other selected frequency), and prevents interference with circuit functioning by external radio-frequency signals.
Yet another feature of the present invention is the use of dual timing blocks to generate waveforms that can be combined to produce an output waveform having selected desired characteristics. In a preferred embodiment of the invention, one of two timing blocks is controlled by the other: that is, the output of the second block is xe2x80x9conxe2x80x9d or xe2x80x9coffxe2x80x9d depending on whether the output of the first block is xe2x80x9clowxe2x80x9d or xe2x80x9chigh,xe2x80x9d respectively. This results in a circuit that generates an output signal whose characteristicsxe2x80x94frequency, duty cycle, amplitudexe2x80x94can be determined over a wide range by the particular selection of components. Two such circuits with output signals having appropriately-selected characteristics can be combined to produce the desired output waveform, with timing intervals T1 through T7, with a surprisingly simple overall circuit configuration.
Another feature of the present invention is the use of conventional, readily-available low-voltage batteries as a power source for the apparatus. This feature not only reduces the size and weight of the apparatus, but also adds to its safety and ease of use for a patient undergoing treatment. Typically, the batteries need to be replaced at infrequent intervals (generally no more than once every few weeks, depending on the output signal and the particular application), simplifying patient compliance and reducing cost. The possibility of electrical injuries is greatly reduced, since the generator is not connected to AC line current during use, does not produce high voltages, and does not generate frequencies likely to induce ventricular fibrillation. Only low power levels are required to produce therapeutic effects; thus, the generator cannot produce an electrical shock hazard even in the event of a malfunction. Thus, the invention is suitable for unsupervised home use.
Still another feature of the present invention is its versatility. The components of the apparatus are selected so as to produce an output waveform with selectable timing intervals T1 through T7 and output voltage (or current) levels L1 through L3. An apparatus with an adjustable output signal is useful for a greater variety of applications than one having a fixed output; on the other hand, medical professionals may prefer a generator having a fixed output, or an output that is adjustable only in magnitude, for outpatient use by their patients. In one embodiment of the invention, the user can select a signal for a given application by turning a dial or using a keypad to select one of a plurality of the available signals noted above.
Other features and advantages of the present invention will be apparent to those skilled in the art from a careful reading of the Detailed Description of Preferred Embodiments presented below and accompanied by the drawings.